Ischemia‐modified albumin in rheumatic diseases: A systematic review and meta‐analysis

Abstract Introduction The identification of novel, easily measurable disease biomarkers might enhance the diagnosis and management of patients with rheumatic diseases (RDs). We conducted a systematic review and meta‐analysis of ischemia‐modified albumin (IMA), a marker of oxidative stress, acidosis, and ischemia, in RD patients and healthy controls. Methods We searched PubMed, Web of Science, and Scopus from inception to January 15, 2024. The risk of bias and the certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. Results In 20 studies investigating a total of 1188 RD patients (mean age 45 years, 64% females) and 981 healthy controls (mean age 44 years, 66% females), RD patients had significantly higher IMA concentrations when compared to controls (standard mean difference, SMD = 0.50, 95% CI: 0.18−0.83, p = .003; I 2 = 92.4%, p < .001; low certainty of evidence). In subgroup analysis, the pooled SMD was significantly different in studies investigating ankylosing spondylitis (p < .001), Behçet's disease (p < .001), and rheumatoid arthritis (p = .033), but not familial Mediterranean fever (p = .48). Further associations were observed between the pooled SMD and the broad classification of autoimmune and/or autoinflammatory diseases, the study country, and the method used to measure IMA. Conclusion Our study suggests that IMA is a promising biomarker of oxidative stress, acidosis, and ischemia, as it can effectively discriminate between patients with different types of RDs and healthy controls. Our results warrant confirmation in longitudinal studies of patients with different types of RDs and different ethnicities (PROSPERO registration number: CRD42024509126).


| INTRODUCTION
The terminology "rheumatic diseases (RDs)" includes a significant number of chronic and disabling conditions characterized by excess inflammation and oxidant stress involving the musculoskeletal system as well as other organs and systems.0][31][32][33][34][35][36][37] One candidate biomarker that has been increasingly studied in RDs over the last 15 years is ischemia-modified albumin (IMA).IMA is generated from chemical modifications targeting the N-terminal sequence of native albumin in the presence of ischemic processes. 38Such chemical modifications can also be triggered by oxidative stress and acidosis. 38Alterations in the concentrations of IMA have been investigated in physiological processes, for example, physical exercise and pregnancy, 39,40 as well as cerebrovascular disease, ischemic heart disease, and heart failure, [41][42][43][44][45][46][47] neurological disorders, 48,49 diabetes mellitus, 50 and cancer. 51,52Given that the formation of IMA reflects, in addition to ischemia, the presence of oxidative stress and acidosis, commonly observed in patients with RDs, [53][54][55][56][57][58][59][60] we assessed the potential role of IMA as a biomarker by conducting a systematic review and meta-analysis of circulating IMA concentrations in RD patients and healthy controls.We speculated that RD patients had significantly higher IMA concentrations compared to healthy controls, highlighting the potential diagnostic role of IMA in RDs.

| Search strategy, inclusion criteria, and study selection
We systematically searched the electronic databases PubMed, Web of Science, and Scopus from inception to January 15, 2024, using the following terms: "IMA" OR "ischemia modified albumin" OR "ischemia-modified albumin" AND "rheumatic diseases" OR "rheumatoid arthritis" OR "psoriatic arthritis" OR "reactive arthritis" OR "ankylosing spondylitis" OR "systemic lupus erythematosus" OR "systemic sclerosis" OR "scleroderma" OR "Sjogren's syndrome" OR "connective tissue diseases" OR "vasculitis" OR "Behçet's disease" OR "idiopathic inflammatory myositis" OR "polymyositis" OR "dermatomyositis" OR "gout" OR "pseudogout" OR "systemic vasculitis" OR "ANCAassociated vasculitis" OR "Takayasu's arteritis" OR "polyarteritis nodosa" OR "osteoarthritis" OR "fibromyalgia" OR "granulomatous polyangiitis" OR "Henoch-Schonlein purpura" OR "Wegener's granulomatosis" OR "familial Mediterranean fever".Two independent investigators screened each abstract and, if potentially relevant, the full-text article according to the following inclusion criteria: (i) measurement of IMA in plasma or serum, (ii) comparison between RD patients and healthy controls using a case-control design, (iii) age ≥18 years, (iv) use of English language, and (v) availability of the full-text of the article.The references of individual articles were hand-searched for additional studies.
The following variables were independently extracted from each article and transferred to an electronic spreadsheet for further analysis: year of publication, first author, type of RD, the country where the study was conducted, number of participants, age, male-to-female ratio, body mass index (BMI), CRP, ESR, mean RD duration, and analytical method used to measure IMA.
We used the Joanna Briggs Institute Critical Appraisal Checklist for analytical studies to assess the risk of bias, 61 and the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group system to assess the certainty of evidence. 62We complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIS-MA) 2020 statement (Tables S1 and S2), 63 and registered the study protocol in an international register (PROS-PERO registration number: CRD42024509126).

| Statistical analysis
We calculated standardized mean differences (SMDs) and 95% confidence intervals (CIs) to generate forest plots of continuous data and to assess possible differences in IMA concentrations between RD patients and healthy controls (statistical significance was set at a p-value < .05).If necessary, means and standard deviations were calculated from medians and interquartile ranges or from medians and ranges using published methods 64 or the Graph Data Extractor Software.Heterogeneity of the SMD across studies was investigated using the Q statistic (significance level at p < .10),and a random-effect model based on the inverse-variance method was used in the presence of high heterogeneity. 65,66Sensitivity analysis was performed to confirm the stability of the results of the meta-analysis. 67ublication bias was investigated using the Begg's adjusted rank correlation test and the Egger's regression asymmetry test (statistical significance was set at a p-value < .05). 68,69e performed univariate meta-regression and subgroup analyses to assess possible associations between the effect size and year of publication, type of RD, study country, sample size, age, male-to-female ratio, BMI, CRP, ESR, mean RD duration, and method used to measure IMA.Statistical analyses were performed using Stata 14 (Stata Corp.).

| Results of the meta-analysis
The forest plot showed that IMA concentrations were significantly higher in RD patients taken as a whole when compared to controls (SMD = 0.50, 95% CI: 0.18−0.83,p = .003;I 2 = 92.4%,p < .001; Figure 2).Sensitivity analysis confirmed the stability of the results, with corresponding pooled SMD values ranging between 0.43 and 0.61 (Figure 3).

| Publication bias
There was no significant publication bias according to either the Begg's (p = .17)or the Egger's (p = .21)test.
F I G U R E 3 Sensitivity analysis of the association between ischemia-modified albumin and rheumatic diseases.

| Certainty of evidence
The overall level of certainty remained low (rating 2) after considering the low-moderate risk of bias in F I G U R E 4 Bubble plot reporting the univariate meta-regression analysis between the effect size and C-reactive protein (CRP) (A) and cumulative meta-analysis of ischemia-modified albumin concentrations based on CRP concentrations (B).virtually all studies (no change), the high but partially explainable heterogeneity (no change), the lack of indirectness (no change), the moderate effect size (SMD = 0.50, no change), and the absence of publication bias (no change).

| DISCUSSION
In our systematic review and meta-analysis, IMA concentrations were significantly higher in RD patients taken as a whole when compared to healthy controls.However, these F I G U R E 5 Forest plot of studies investigating ischemia-modified albumin in patients with rheumatic diseases and healthy controls according to the type of rheumatic disease.
F I G U R E 6 Forest plot of studies investigating ischemia-modified albumin in patients with rheumatic diseases and healthy controls according to the presence of autoimmune, mixed autoimmune-autoinflammatory, and autoinflammatory diseases.
alterations differed according to specific RDs and broad RD categories.Specifically, the between-group differences in IMA concentrations versus controls were significant in patients with AS, BD, and RA but not in patients with FMF.Furthermore, they were significant in patients with mixed autoimmune-autoinflammatory diseases but not in those with autoimmune or autoinflammatory diseases.In meta-regression analysis, there were no significant associations between the effect size of the between-group differences and various patient and study characteristics, particularly ESR, CRP, and mean RD duration.These observations suggest that the information provided by measuring IMA concentrations does not simply replicate that provided by conventional markers of F I G U R E 7 Forest plot of studies investigating ischemia-modified albumin in patients with rheumatic diseases and healthy controls according to the country where the study was conducted.
F I G U R E 8 Forest plot of studies investigating ischemia-modified albumin in patients with rheumatic diseases and healthy controls according to the analytical method used to measure ischemia-modified albumin.
inflammation and that the between-group differences in IMA concentrations are also evident in patients with relatively short RD duration, supporting the potential clinical utility of IMA as a biomarker of early RDs.Further subgroup analyses highlighted the presence of significant differences in the pooled SMD in studies conducted in Turkey but not in other countries and the potential influence of the analytical method used in determining the between-group differences in IMA concentrations.
Although there is ongoing uncertainty regarding the exact chemical reactions involved during the biotransformation of native albumin into IMA in the context of an ischemic event, the opposite biotransformation, with the regeneration of albumin, is common following ischemia. 38,90In subgroup analysis, the pooled SMD was significantly different using the ACB assay and automatic analyzers, but not ELISA.These methods are generally characterized by high sensitivity and specificity however they are not yet available for routine clinical use. 38The majority of studies selected in our systematic review and meta-analysis, 14 out of 20, used the ABC method. 91owever, the results with this method may be influenced by pH fluctuations, denaturing agents, or specific pharmacological agents. 38Furthermore, IMA concentrations are commonly expressed as absorbance units, which may depend on operator experience and/or the sensitivity of the equipment, and internal standards have been obtained by some investigators in their laboratories. 38Although these factors might account for the high heterogeneity in our meta-analysis it should also be emphasized that no consensus exists regarding the exact chemical reactions involved in the biotransformation of albumin into IMA. 38To address these issues, methods based on immunological reactions using antibodies to IMA are being investigated. 382][43][44][45][46] However, significant alterations in IMA concentrations have also been reported in congestive heart failure, 47 neurodegenerative disorders, 48 pregnancy disorders, 92 and cancer. 524][55][56][57][58][59][60] Regardless of the exact biochemical and cellular mechanisms responsible for the increased IMA concentrations in RD patients, prospective studies should investigate whether IMA can enhance the diagnosis, monitoring, and management in this patient group before introducing its measurement in routine practice.
Our study has several strengths, including the assessment of IMA in patients with several types of RDs and broad RD classifications, the investigation of possible associations between the effect size of the between-group differences in IMA concentrations, and several study and patient characteristics, particularly CRP, ESR, and RD duration, and a comprehensive assessment of the risk of bias and the certainty of evidence.Furthermore, the results of the meta-analysis were stable in sensitivity analysis.However, important limitations should also be acknowledged, including the relatively limited number of RDs analyzed (SSc, RA, FMF, fibromyalgia, BD, AS, IgAV, SS, OA, AAV, and SLE) and the fact that the majority of studies, 16 out of 20, were conducted in Turkey, which curtails the generalizability of the results.This issue requires addressing in further research, also given that some evidence suggests the presence of significant differences in IMA concentrations between ethnic groups. 98

| CONCLUSIONS
Taken together, the results of our systematic review and meta-analysis expand the current knowledge regarding the pathophysiological and diagnostic role of IMA, suggesting its potential utility as a biomarker of RDs, including patients with early forms of the disease.However, additional research is required to confirm these observations, to investigate the presence of similar alterations in patients with other types of RDs and different ethnicity, and to determine whether IMA can enhance diagnosis, monitoring, and management in prospective studies before its introduction in clinical practice.

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I G U R E 1 PRISMA 2020 flow diagram.T A B L E 1 Characteristics of the studies investigating ischemia-modified albumin in patients with rheumatic diseases and healthy controls.al. 2016, Turkey75 Assessment of the risk of bias using the Joanna Briggs Institute critical appraisal checklist.